Brain uptake of local anesthetics under steady-state plasma condition and/or following intravenous bolus administration was investigated in rats. All ester-type anesthetics examined such as ethyl (Et), propyl (Pr), butyl (Bu) esters of p-aminobenzoic acid (PABA), and procaine disappeared rapidly from plasma in a dose-dependent manner. Plasma profiles of these compounds were well explained by a 2-compartment model with a Michaelis-Menten type elimination process from a central compartment. On the other hand, lidocaine, amide-type anesthetic, showed a linear pharmacokinetic characteristic and its half life in the elimination phase was far longer than those of ester type agents. Extents of brain uptake (brain-to-plasma partition coefficient, K_p value) of these drugs were determined at 3 different steady-state plasma concentrations (1-15μM). The K_p value of each drug was similar under the three different steady-state plasma concentrations. The K_p value increased in the following order ; procaine (1.1)<PABA-Et (1.9)<lidocaine (2.2)<PABA-Pr (2.7)<PABA-Bu (3.6). A linear relationship was observed between the K_p value and the logarithmic value of the partition coefficient obtained in n-heptane/water or n-octanol/water partition system. The value of PABA-Et and PABA-Bu following intravenous bolus administration were varied with time elapsed but the mean values were almost same with those obtained under steady-state plasma conditions.

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Plasma levels of haloperidol decanoate and haloperidol after intramuscular administration of haloperidol decanoate in rats showed good fits with a multi-compartment model which was constituted by combination of 2-compartment models for the disposition of haloperidol and for its ester decanoate through the process of hydrolysis of the ester. Calculated parameters indicated that most of intramuscularly administered haloperidol decanoate is absorbed in blood after hydrolysis to haloperidol and the absorption is rate-limiting. Regional lymph node levels suggested that the intramuscularly administered ester was absorbed via the lymphatic system where the hydrolysis to haloperidol probably occurred. Thus, slow entrance and hydrolysis of haloperidol decanoate in the lymphatic system was considered to be the cause of sustained plasma levels of the active principle after intramuscular administration of haloperidol decanoate.

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Uricase (UC) was conjugated with dextran, cationic diethylaminoethyl-dextran (DEAED), and anionic carboxymethyl-dextran (CMD) giving a molecular weight of 10000 by the periodate oxidation method. Their disposition characteristics were studied after intravenous injection (i.v.) in mice. Disposition of the conjugate with activated polyethylene glycol (PEG₂) with a similar molecular weight was also studied for comparison. Tissue distribution of the ¹¹¹In-labeled UC in these conjugates was evaluated by a tissue uptake clearance index calculated in terms of clearance. After i.v. injection, ¹¹¹In-UC was slowly eliminated from the circulation and gradually accumulated in the liver, spleen, and kidney. Conjugation with neutral dextran slightly enhanced the uptake of ¹¹¹In-UC by the liver and spleen, while PEG₂ conjugation decreased the tissue uptake and resulted in extremely long plasma retention. On the other hand, DEAED and CMD conjugation resulted in significant enhancement and reduction of hepatic uptake, respectively. These results demonstrated that the pharmacokinetic behaviour of UC can be widely controlled by chemical modification with macromolecules having adequate physicochemical properties.

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Platelet proteo-chondroitin sulfates localize on the surface and in the granules. Western blotting method is able to selectively detect core-proteins prepared from proteo-chondroitin sulfates by chondroitinase ABC digestion. A very highly sensitive high-performance liquid chromatographic method was established for the determination of chondroitin sulfates as their unsaturated disaccharides. These methods were applied to rabbit platelet proteo-chondroitin sulfates. It was found that both rabbit platelet surface proteo-chondroitin sulfate and granule proteo-chondroitin sulfate consist of a predominantly homogeneous chondroitin 4-sulfate and a single core-protein having a molecular weight of approximately 26 kDa.

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Subanalgesic dose, 0.01 to 0.25 mg/kg, of clonidine (CLO), an α₂-adrenoceptor agonist, potentiated forced swimming (SW) stress induced analgesia (SIA) and suppressed psychological (PSY)-SIA in a dose dependent manner but did not affect foot-shock (FS)-SIA. Daily exposure to each stress rapidly developed tolerance, and the development was suppressed by daily concomitant subanalgesic dose of CLO in SW-SIA but not in FS- and PSY-SIA. Meanwhile, SW-stress, applied after injection of CLO, 1 mg/kg, potentiated the analgesic effect of CLO and suppressed the development of tolerance to the effect. On the other hand, FS- and PSY-stress did not affect CLO analgesia and failed to block the tolerance development. These results provide further evidence that α₂-adrenergic mechanism is involved in the production of SW-SIA.

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